The present invention relates to a process for the dehydration of substituted 4-dimethylamino-2-aryl-butan-2-ol compounds and to processes for the preparation of substituted dimethyl-(3-aryl-butyl)-amine compounds by heterogeneous catalysis.
Opioids, for example morphine, have been used in the therapy of pain for many years, although they cause a number of side-effects, for example addiction, dependency, respiratory depression, impaired gastro-intestinal motility and constipation. They can therefore be taken for a prolonged period and in relatively high doses only with particular safety measures (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990).
Because of the high demand for a pain therapy that is satisfactory for the patient, the search for new, highly effective and tolerable pain relievers is the focus of medical research.
With the development of substituted dimethyl-(3-aryl-but-3-enyl)-amine compounds, as are described, for example, in EP 0 799 819, it has been possible to make available new pain relievers that are distinguished by very good effectiveness and that exhibit no side-effects or at least side-effects that are markedly reduced compared with conventional pain relievers.
The preparation of these compounds is carried out by dehydration of appropriately substituted 4-dimethylamino-2-aryl-butan-2-ol compounds which have a tertiary alcohol function, using acid, in particular formic acid or hydrochloric acid. This process has the disadvantage that the acid used for the dehydration must subsequently be separated from the reaction mixture by neutralisation and, optionally, repeated extraction.
The resulting salt can lead to equipment corrosion, and side products such as the waste water has a negative effect on the environment, and the production costs of the process is also high. A further class of active ingredients having excellent analgesic effectiveness and very good tolerability are the substituted dimethyl-(3-aryl-butyl)-amine compounds, which are known inter alia from EP 0 693 475.
The preparation of these pharmaceutical active ingredients is likewise carried out starting from tertiary alcohols, which are first converted into the corresponding chloride compound and then reduced with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride. This process has the disadvantage that the preparation of the chloride compound is carried out with the use of comparatively aggressive chlorinating agents such as thionyl chloride. Furthermore, the process does not give a satisfactory yield in all cases.